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Despite the great success of small molecule inhibitors in the treatment of patients with BRAF V600E  mutated melanoma, the response to these drugs remains transient and patients eventually relapse within a few months, highlighting the need to develop novel combination therapies based on the understanding of the molecular changes induced by BRAF V600E  inhibitors. The acute inhibition of oncogenic signaling can rewire entire cellular signaling pathways and thereby create novel cancer cell vulnerabilities. Here, we demonstrate that inhibition of BRAF V600E  oncogenic signaling in melanoma cell lines leads to destabilization of the large subunit of RNA polymerase II POLR2A ( pol ymerase  R NA  II  DNA-directed polypeptide  A ), thereby preventing its binding to the  u nconventional prefoldin  RP B5  i nteractor (URI1) chaperone complex and the successful assembly of RNA polymerase II holoenzymes. Furthermore, in melanoma cell lines treated with mitogen-activated protein kinase (MAPK) inhibitors, α-amanitin, a specific and irreversible inhibitor of RNA polymerase II, induced massive apoptosis. Pre-treatment of melanoma cell lines with MAPK inhibitors significantly reduced IC50 values to α-amanitin, creating a state of collateral vulnerability similar to  POLR2A  hemizygous deletions. Thus, the development of melanoma specific α-amanitin antibody-drug conjugates could represent an interesting therapeutic approach for combination therapies with BRAF V600E  inhibitors.

BRAF inhibition sensitizes melanoma cells to α-amanitin via decreased RNA polymerase II assembly